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Depression: HELP
Articles by Richard C. Shelton
Based on 86 articles published since 2008

Between 2008 and 2019, Richard Shelton wrote the following 86 articles about Depression.
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Editorial The Course of Illness After Initial Diagnosis of Major Depression. 2016

Shelton, Richard C. ·Department of Psychiatry and Behavioral Neurobiology, The University of Alabama at Birmingham. ·JAMA Psychiatry · Pubmed #26934634.

ABSTRACT: -- No abstract --

2 Editorial Does concomitant use of NSAIDs reduce the effectiveness of antidepressants? 2012

Shelton, Richard C. · ·Am J Psychiatry · Pubmed #23032377.

ABSTRACT: -- No abstract --

3 Editorial The role of residual symptoms in nonadherence to treatment. 2009

Shelton, Richard C. ·Vanderbilt University School of Medicine, Nashville, TN, USA. ·CNS Spectr · Pubmed #20448514.

ABSTRACT: -- No abstract --

4 Review Interaction between early-life stress and FKBP5 gene variants in major depressive disorder and post-traumatic stress disorder: A systematic review and meta-analysis. 2018

Wang, Qingzhong / Shelton, Richard C / Dwivedi, Yogesh. ·Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. · Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: ydwivedi@uab.edu. ·J Affect Disord · Pubmed #28850857.

ABSTRACT: BACKGROUND: Gene-environment interaction contributes to the risks of psychiatric disorders. Interactions between FKBP5 gene variants and early-life stress may enhance the risk not only for mood disorder, but also for a number of other behavioral phenotypes. The aim of the present study was to review and conduct a meta-analysis on the results from published studies examining interaction between FKBP5 gene variants and early-life stress and their associations with stress-related disorders such as major depression and PTSD. METHODS: A literature search was conducted using PsychINFO and PubMed databases until May 2017. A total of 14 studies with a pooled total of 15109 participants met the inclusion criteria, the results of which were combined and a meta-analysis was performed using the differences in correlations as the effect measure. Based on literature, rs1360780, rs3800373, and rs9470080 SNPs were selected within the FKBP5 gene and systematic review was conducted. RESULTS: Based on the Comprehensive Meta-Analysis software, no publication bias was detected. Sensitivity analysis and credibility of meta-analysis results also indicated that the analyses were stable. The meta-analysis showed that individuals who carry T allele of rs1360780, C-allele of rs3800373 or T-allele of rs9470080 exposed to early-life trauma had higher risks for depression or PTSD. LIMITATIONS: The effects of ethnicity, age, sex, and different stress measures were not examined due to limited sample size. CONCLUSIONS: These results provide strong evidence of interactions between FKBP5 genotypes and early-life stress, which could pose a significant risk factor for stress-associated disorders such as major depression and PTSD.

5 Review Treatment resistant depression: strategies for primary care. 2013

Preston, Taylor C / Shelton, Richard C. ·Department of Psychiatry and Behavioral Neurobiology, The University of Alabama at Birmingham, SC 1026 1720 2nd Ave S, Birmingham, AL 35294-0018, USA. ·Curr Psychiatry Rep · Pubmed #23712721.

ABSTRACT: Depression is commonly diagnosed and treated in primary care. Recent evidence indicates that the majority of depressed patients will not fully recover with an initial antidepressant treatment. This paper reviews commonly used options for treatment after an inadequate initial antidepressant response. The alternatives range widely, and include escalating the dose of the initial antidepressant, switching to an alternative medication, combining two antidepressants with different mechanisms of action (e.g., bupropion + SSRI or mirtazapine + venlafaxine), adding other medications such as lithium or certain atypical antipsychotics (olanzapine, aripiprazole, or quetiapine) to the antidepressant, adding a natural product such as l-methylfolate or s-adenosylmethionine (SAMe), or adding cognitive behavioral psychotherapy. What agent to be used will depend on the comfort level of the primary care practitioner and the availability of Psychiatry referral. However, it is reasonable to take one or more additional steps to attempt to achieve remission.

6 Review Agomelatine for the treatment of major depressive disorder. 2011

Carney, Regina M / Shelton, Richard C. ·Vanderbilt University Medical Center, Department of Psychiatry, 1500 21st Avenue, South, Suite 2200, Nashville, TN 37212, USA. ·Expert Opin Pharmacother · Pubmed #21916789.

ABSTRACT: INTRODUCTION: This article discusses agomelatine (Valdoxan(™)/Thymanax(™); Servier/Novartis), which is a melatonin (MT1/MT2) agonist and serotonin (5-HT2c) receptor antagonist. Agomelatine has been approved for the treatment of adults with major depression by several regulatory agencies and is now on the market in 41 countries. AREAS COVERED: Literature related to agomelatine was reviewed on PubMed using the search terms 'agomelatine OR S-20098' and 204 articles were found. Twelve published, randomized, double-blind studies were included in this review. EXPERT OPINION: Agomelatine produces strong effects on circadian sleep phase disturbances, improving time to sleep onset and quality of sleep. It has been shown to be superior to placebo and similar to existing antidepressants, as demonstrated by short-term clinical trials and one relapse prevention trial. However, 0 - 0.6% and 3 - 4.5% of patients treated with 25 and 50 mg, respectively, showed elevated transaminases. Although none of these reactions so far seem to have been serious, the adverse effects in the liver may present a regulatory and marketing challenge. Given equivalence or modest superiority to existing, generic alternatives, the acceptability in a third-party reimbursement environment is questionable. Future clinical trials are needed to establish an appropriate market niche.

7 Review Functional biomarkers of depression: diagnosis, treatment, and pathophysiology. 2011

Schmidt, Heath D / Shelton, Richard C / Duman, Ronald S. ·Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. hschmidt@mail.med.upenn.edu ·Neuropsychopharmacology · Pubmed #21814182.

ABSTRACT: Major depressive disorder (MDD) is a heterogeneous illness for which there are currently no effective methods to objectively assess severity, endophenotypes, or response to treatment. Increasing evidence suggests that circulating levels of peripheral/serum growth factors and cytokines are altered in patients with MDD, and that antidepressant treatments reverse or normalize these effects. Furthermore, there is a large body of literature demonstrating that MDD is associated with changes in endocrine and metabolic factors. Here we provide a brief overview of the evidence that peripheral growth factors, pro-inflammatory cytokines, endocrine factors, and metabolic markers contribute to the pathophysiology of MDD and antidepressant response. Recent preclinical studies demonstrating that peripheral growth factors and cytokines influence brain function and behavior are also discussed along with their implications for diagnosing and treating patients with MDD. Together, these studies highlight the need to develop a biomarker panel for depression that aims to profile diverse peripheral factors that together provide a biological signature of MDD subtypes as well as treatment response.

8 Review Efficacy, safety and tolerability of Symbyax for acute-phase management of treatment-resistant depression. 2010

Bobo, William V / Shelton, Richard C. ·Department of Psychiatry, Vanderbilt University School of Medicine, South Suite 2200, Village at Vanderbilt, Nashville, TN 37212, USA. william.v.bobo@vanderbilt.edu ·Expert Rev Neurother · Pubmed #20420487.

ABSTRACT: Treatment resistance is frequently encountered during the long-term care of patients with major depression. A number of 'next step' therapeutic options exist in such cases, including switching to an alternative antidepressant, combining antidepressants from different pharmacological classes, adding evidence-supported psychotherapies to ongoing antidepressant treatment and augmentation with a nonantidepressant drug. Augmenting antidepressants with atypical antipsychotic drugs has generated considerable clinical interest. Three atypical antipsychotics (aripiprazole, quetiapine and olanzapine) have received regulatory approval for adjunctive use with antidepressants for treatment-resistant major depression (TRD) in adults. Symbyax (olanzapine-fluoxetine combination or OFC), the combination of olanzapine and the selective serotonin-reuptake inhibitor fluoxetine, is also approved for this indication. The short-term effectiveness of OFC for TRD is supported by results of five published randomized, controlled, acute-phase studies of generally similar design. In each study, OFC was associated with rapid reduction in depressive symptoms. In two studies, significantly greater improvement in depressive symptoms occurred in OFC-treated patients at study end point compared with those who received antidepressant monotherapy. These effects appeared to be strongest in cases where antidepressant failure was established during the current depressive episode. Although OFC was well-tolerated, increases in body weight and prolactin concentration were greater with OFC than antidepressant monotherapy, and were similar to olanzapine monotherapy. Increases in random total cholesterol levels were greatest for OFC, and were significantly greater than those of olanzapine and antidepressant monotherapy. The long-term efficacy and tolerability of OFC for TRD has not been investigated, and the comparative effectiveness of OFC versus other next-step options is unknown. As such, the exact place of OFC among the available therapeutic options for TRD is not fully understood at this time.

9 Review Eating ourselves to death (and despair): the contribution of adiposity and inflammation to depression. 2010

Shelton, Richard C / Miller, Andrew H. ·Vanderbilt University, 1500 21st Avenue South, Suite 2200, Nashville, TN 37212, USA. richard.shelton@vanderbilt.edu ·Prog Neurobiol · Pubmed #20417247.

ABSTRACT: Obesity and related metabolic conditions are of epidemic proportions in most of the world, affecting both adults and children. The accumulation of lipids in the body in the form of white adipose tissue in the abdomen is now known to activate innate immune mechanisms. Lipid accumulation causes adipocytes to directly secrete the cytokines interleukin (IL) 6 and tumor necrosis factor alpha (TNFalpha), but also monocyte chemoattractant protein 1 (MCP-1), which results in the accumulation of leukocytes in fat tissue. This sets up a chronic inflammatory state which is known to mediate the association between obesity and conditions such as cardiovascular disease, type 2 diabetes, and cancer. There is also a substantial literature linking inflammation with risk for depression. This includes the observations that: (1) people with inflammatory diseases such as multiple sclerosis, cardiovascular disease, and psoriasis have elevated rates of depression; (2) many people administered inflammatory cytokines such as interferon alpha develop depression that is indistinguishable from depression in non-medically ill populations; (3) a significant proportion of depressed persons show upregulation of inflammatory factors such as IL-6, C-reactive protein, and TNFalpha; (4) inflammatory cytokines can interact with virtually every pathophysiologic domain relevant to depression, including neurotransmitter metabolism, neuroendocrine function, and synaptic plasticity. While many factors may contribute to the association between inflammatory mediators and depression, we hypothesize that increased adiposity may be one causal pathway. Mediational analysis suggests a bi-directional association between adiposity and depression, with inflammation possibly playing an intermediary role.

10 Review Therapeutic options for treatment-resistant depression. 2010

Shelton, Richard C / Osuntokun, Olawale / Heinloth, Alexandra N / Corya, Sara A. ·Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. ·CNS Drugs · Pubmed #20088620.

ABSTRACT: Treatment-resistant depression (TRD) presents major challenges for both patients and clinicians. There is no universally accepted definition of TRD, but results from the US National Institute of Mental Health's (NIMH) STAR*D (Sequenced Treatment Alternatives to Relieve Depression) programme indicate that after the failure of two treatment trials, the chances of remission decrease significantly. Several pharmacological and nonpharmacological treatments for TRD may be considered when optimized (adequate dose and duration) therapy has not produced a successful outcome and a patient is classified as resistant to treatment. Nonpharmacological strategies include psychotherapy (often in conjunction with pharmacotherapy), electroconvulsive therapy and vagus nerve stimulation. The US FDA recently approved vagus nerve stimulation as adjunctive therapy (after four prior treatment failures); however, its benefits are seen only after prolonged (up to 1 year) use. Other nonpharmacological options, such as repetitive transcranial stimulation, deep brain stimulation or psychosurgery, remain experimental and are not widely available. Pharmacological treatments of TRD can be grouped in two main categories: 'switching' or 'combining'. In the first, treatment is switched within and between classes of compounds. The benefits of switching include avoidance of polypharmacy, a narrower range of treatment-emergent adverse events and lower costs. An inherent disadvantage of any switching strategy is that partial treatment responses resulting from the initial treatment might be lost by its discontinuation in favour of another medication trial. Monotherapy switches have also been shown to have limited effectiveness in achieving remission. The advantage of combination strategies is the potential to build upon achieved improvements; they are generally recommended if partial response was achieved with the current treatment trial. Various non-antidepressant augmenting agents, such as lithium and thyroid hormones, are well studied, although not commonly used. There is also evidence of efficacy and increasing use of atypical antipsychotics in combination with antidepressants, for example, olanzapine in combination with fluoxetine (OFC) or augmentation with aripiprazole. The disadvantages of a combination strategy include multiple medications, a broader range of treatment-emergent adverse events and higher costs. Several experimental pharmaceutical treatment alternatives for TRD are also being explored in combination with antidepressants or as monotherapy. These less studied alternative compounds include pindolol, inositol, CNS stimulants, hormones, herbal supplements, omega-3 fatty acids, S-adenosyl-L-methionine, folic acid, lamotrigine, modafinil, riluzole and topiramate. In summary, despite an increasing variety of choices for the treatment of TRD, this condition remains universally undefined and represents an area of unmet medical need. There are few known approved pharmacological agents for TRD (aripiprazole and OFC) and overall outcomes remain poor. This might be an indication that depression itself is a heterogeneous condition with a great diversity of pathologies, highlighting the need for careful evaluation of individuals with depressive symptoms who are unresponsive to treatment. Clearly, more research is needed to provide clinicians with better guidance in making those treatment decisions--especially in light of accumulating evidence that the longer patients are unsuccessfully treated, the worse their long-term prognosis tends to be.

11 Review Antidepressant drug effects and depression severity: a patient-level meta-analysis. 2010

Fournier, Jay C / DeRubeis, Robert J / Hollon, Steven D / Dimidjian, Sona / Amsterdam, Jay D / Shelton, Richard C / Fawcett, Jan. ·Department of Psychology, University of Pennsylvania, 3720 Walnut St, Philadelphia, PA 19104, USA. jcf@sas.upenn.edu ·JAMA · Pubmed #20051569.

ABSTRACT: CONTEXT: Antidepressant medications represent the best established treatment for major depressive disorder, but there is little evidence that they have a specific pharmacological effect relative to pill placebo for patients with less severe depression. OBJECTIVE: To estimate the relative benefit of medication vs placebo across a wide range of initial symptom severity in patients diagnosed with depression. DATA SOURCES: PubMed, PsycINFO, and the Cochrane Library databases were searched from January 1980 through March 2009, along with references from meta-analyses and reviews. STUDY SELECTION: Randomized placebo-controlled trials of antidepressants approved by the Food and Drug Administration in the treatment of major or minor depressive disorder were selected. Studies were included if their authors provided the requisite original data, they comprised adult outpatients, they included a medication vs placebo comparison for at least 6 weeks, they did not exclude patients on the basis of a placebo washout period, and they used the Hamilton Depression Rating Scale (HDRS). Data from 6 studies (718 patients) were included. DATA EXTRACTION: Individual patient-level data were obtained from study authors. RESULTS: Medication vs placebo differences varied substantially as a function of baseline severity. Among patients with HDRS scores below 23, Cohen d effect sizes for the difference between medication and placebo were estimated to be less than 0.20 (a standard definition of a small effect). Estimates of the magnitude of the superiority of medication over placebo increased with increases in baseline depression severity and crossed the threshold defined by the National Institute for Clinical Excellence for a clinically significant difference at a baseline HDRS score of 25. CONCLUSIONS: The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial.

12 Review Long-term management of depression: tips for adjusting the treatment plan as the patient's needs change. 2009

Shelton, Richard C. ·Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. richard.shelton@vanderbilt.edu ·J Clin Psychiatry · Pubmed #19922742.

ABSTRACT: Depression is a difficult-to-treat condition. Most individuals with depression do not achieve remission with any single treatment, and, when they do achieve remission, the majority will have residual symptoms. Therefore, clinicians must be prepared to aggressively manage relapse and recurrence throughout all phases of treatment. The ultimate goals for the long-term treatment of depression are to (1) help the patient achieve remission, (2) keep the patient as asymptomatic as possible, and (3) manage risk factors for subsequent episodes. Psychotherapies and pharmacotherapies appear to have dissimilar mechanisms of action and produce different effects in depression; psychotherapy, particularly cognitive-behavioral therapy and behavioral activation therapy, may have more of a relapse prevention effect than pharmacotherapy. Because chronicity and recurrence are the rule rather than the exception, clinicians should choose treatments that have shown efficacy for protecting against future episodes. In addition, factors such as comorbidities and stressful life events increase the likelihood of depressive relapse; thus, these problems must be addressed to prevent a full relapse. By anticipating and adjusting treatment to meet patients' changing needs over time, clinicians can help them achieve and maintain remission from depression.

13 Review St John's wort (Hypericum perforatum) in major depression. 2009

Shelton, Richard C. ·Department of Psychiatry, Mood Disorders Program, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. richard.shelton@vanderbilt.edu ·J Clin Psychiatry · Pubmed #19909690.

ABSTRACT: The herb St John's wort (Hypericum perforatum) has been used for centuries to treat a variety of medical illnesses. In certain areas of Europe, St John's wort has been a commonly prescribed treatment for depression, but, in the United States, it is available for purchase over the counter as an herbal supplement. Some researchers believe that specific chemical constituents of St John's wort produce change in depression in a way similar to that of antidepressant medications, yet this hypothesis is problematic. In addition, studies that support the efficacy of St John's wort in patients with mild-to-moderate depression have limitations that may affect the accuracy of their conclusions. Studies measuring the effect of St John's wort in major depression have reported conflicting results and need to be reexamined. Because St John's wort is considered by some to be an alternative to conventional therapies, clinicians need to know whether it is an effective and safe treatment for different levels of severity of depression. Current evidence does not support its use, and, because of potential drug interactions, St John's wort is not a benign treatment.

14 Review Fluoxetine and olanzapine combination therapy in treatment-resistant major depression: review of efficacy and safety data. 2009

Bobo, William Victor / Shelton, Richard C. ·Vanderbilt University School of Medicine, Department of Psychiatry, 1500 21st Ave South, Village at Vanderbilt, Nashville, TN 37212, USA. william.v.bobo@vanderbilt.edu ·Expert Opin Pharmacother · Pubmed #19640209.

ABSTRACT: BACKGROUND: There has been growing evidence supporting the use of atypical antipsychotic drugs as adjunctive treatments in patients with major depression who fail to respond adequately to antidepressants. OBJECTIVE: To review the efficacy and safety data for one such combination, fluoxetine (FLX) + olanzapine (OLZ) in treatment-resistant depression (TRD). METHODS: We reviewed published randomized, controlled acute-phase studies, as well as available long-term clinical studies. RESULTS/CONCLUSIONS: In each acute-phase study (n = 5), FLX/OLZ group experienced rapid antidepressant effects and, in two of these studies, resulted in significantly greater improvement at study end point compared with antidepressant monotherapy. These effects were strongest when TRD was defined as having failed at least two antidepressant trials during the current depressive episode. FLX + OLZ was generally well tolerated; however, increases in body weight and prolactin levels with FLX + OLZ were greater than that of antidepressant monotherapy groups and were similar to OLZ monotherapy. However, changes in random total cholesterol were also greatest for FLX + OLZ and were greater in magnitude than that of OLZ or FLX monotherapy. Long-term effectiveness/safety data are sparse, and comparison trials and sequential treatment studies involving FLX + OLZ and other antidepressant-atypical antipsychotic combinations are lacking. Thus, the exact place of FLX + OLZ among other available options for TRD is difficult to determine.

15 Review Use of atypical antipsychotics for treatment-resistant major depressive disorder. 2008

Papakostas, George I / Shelton, Richard C. ·Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, WACC #812, Boston, MA 02114, USA. gpapakostas@partners.org ·Curr Psychiatry Rep · Pubmed #18980731.

ABSTRACT: Despite the progressive increase in the number of pharmacologic agents with potential antidepressant activity, many patients suffering from major depressive disorder (MDD) continue to be symptomatic. Clearly, an urgent need exists to develop safer, better tolerated, and more effective treatments for MDD. Use of atypical antipsychotic agents as adjunctive treatment for treatment-resistant MDD (TRD) represents one such effort toward novel pharmacotherapy development. Atypical antipsychotic agents have been hypothesized to be beneficial in treating mood disorders, including TRD, as a result of their complex mechanisms of action. After an initial series of positive case reports, series, and small clinical trials, subsequent larger-scale projects have yielded conflicting results. However, more recently, larger-scale clinical trials have supported the effectiveness of at least some of these medications. This review summarizes the existing data regarding the effectiveness of these medications in treating TRD, including biochemical rationale and clinical data.

16 Review Augmentation of antidepressants with atypical antipsychotics for treatment-resistant major depressive disorder. 2008

Shelton, Richard C / Papakostas, George I. ·Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA. richard.shelton@vanderbilt.edu ·Acta Psychiatr Scand · Pubmed #18190674.

ABSTRACT: OBJECTIVE: Atypical antipsychotics (AAPs) have been hypothesized to be beneficial in treatment-resistant depression (TRD). This paper will review a biochemical rationale and will summarize the data regarding the effectiveness of AAPs in TRD. METHOD: Studies were identified using searches of Pubmed/Medline, EMBase and the Cochrane databases by cross-referencing the term 'depression' with each of the six AAPs. RESULTS: After initial positive, short case reports and clinical trials, larger studies failed to show the effectiveness of AAPs combined with antidepressants for TRD. More recently, larger scale clinical trials have supported the effectiveness of at least some of these medications. While AAPs have gained in popularity for TRD, there are nagging concerns regarding risks such as metabolic syndrome and tardive dyskinesia. CONCLUSION: The existing research provides some support for the beneficial effects of AAPs when combined with SSRI's in TRD. These medications pose significant risks that must be considered in their use.

17 Clinical Trial A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression. 2016

Singh, Jaskaran B / Fedgchin, Maggie / Daly, Ella J / De Boer, Peter / Cooper, Kimberly / Lim, Pilar / Pinter, Christine / Murrough, James W / Sanacora, Gerard / Shelton, Richard C / Kurian, Benji / Winokur, Andrew / Fava, Maurizio / Manji, Husseini / Drevets, Wayne C / Van Nueten, Luc. ·From Janssen Research and Development, Titusville, N.J., and Beerse, Belgium; the Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, N.Y.; the Department of Psychiatry, Yale University, New Haven, Conn.; the Department of Psychiatry and Behavioral Neurobiology, School of Medicine, University of Alabama at Birmingham; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Institute of Living, Hartford, Conn.; University of Connecticut Health Center, Farmington; the Department of Psychiatry, Massachusetts General Hospital, Boston. ·Am J Psychiatry · Pubmed #27056608.

ABSTRACT: OBJECTIVE: Ketamine, an N-methyl-d-aspartate glutamate receptor antagonist, has demonstrated a rapid-onset antidepressant effect in patients with treatment-resistant depression. This study evaluated the efficacy of twice- and thrice-weekly intravenous administration of ketamine in sustaining initial antidepressant effects in patients with treatment-resistant depression. METHOD: In a multicenter, double-blind study, adults (ages 18-64 years) with treatment-resistant depression were randomized to receive either intravenous ketamine (0.5 mg/kg of body weight) or intravenous placebo, administered over 40 minutes, either two or three times weekly, for up to 4 weeks. Patients who discontinued double-blind treatment after at least 2 weeks for lack of efficacy could enter an optional 2-week open-label phase to receive ketamine with the same frequency as in the double-blind phase. The primary outcome measure was change from baseline to day 15 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: In total, 67 (45 women) of 68 randomized patients received treatment. In the twice-weekly dosing groups, the mean change in MADRS score at day 15 was -18.4 (SD=12.0) for ketamine and -5.7 (SD=10.2) for placebo; in the thrice-weekly groups, it was -17.7 (SD=7.3) for ketamine and -3.1 (SD=5.7) for placebo. Similar observations were noted for ketamine during the open-label phase (twice-weekly, -12.2 [SD=12.8] on day 4; thrice-weekly, -14.0 [SD=12.5] on day 5). Both regimens were generally well tolerated. Headache, anxiety, dissociation, nausea, and dizziness were the most common (≥20%) treatment-emergent adverse events. Dissociative symptoms occurred transiently and attenuated with repeated dosing. CONCLUSIONS: Twice-weekly and thrice-weekly administration of ketamine at 0.5 mg/kg similarly maintained antidepressant efficacy over 15 days.

18 Clinical Trial Assessment of the Efficacy and Safety of BMS-820836 in Patients With Treatment-Resistant Major Depression: Results From 2 Randomized, Double-Blind Studies. 2015

Bhagwagar, Zubin / Torbeyns, Anne / Hennicken, Delphine / Zheng, Ming / Dunlop, Boadie W / Mathew, Sanjay J / Khan, Arif / Weisler, Richard / Nelson, Craig / Shelton, Richard / Thase, Michael E / Lane, Roger. ·From *Bristol-Myers Squibb Company, Wallingford, CT; †Bristol-Myers Squibb Company, Braine-l'Alleud, Belgium; ‡Emory University, Atlanta, GA; §Baylor College of Medicine, Houston, TX; ∥Northwest Clinical Research Center, Bellevue, WA; ¶Department of Psychiatry, Duke University School of Medicine, Durham; #Department of Psychiatry, Duke University Medical Center, Durham; **Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC; ††University of California, San Francisco, CA; ‡‡University of Alabama at Birmingham, Birmingham, AL; and §§University of Pennsylvania, Philadelphia, PA. ·J Clin Psychopharmacol · Pubmed #25961781.

ABSTRACT: Two phase 2B, randomized, double-blind studies assessed the efficacy and safety of fixed or flexible dose of triple monoamine uptake inhibitor BMS-820836 in patients with treatment-resistant depression to demonstrate whether switching to BMS-820836 was superior to the continuation of standard antidepressant treatment. Patients with a history of inadequate response to 1 to 3 adequate trials of antidepressant therapies were prospectively treated with duloxetine 60 mg/d for 8 weeks (CN162-006) or duloxetine 60 mg/d or escitalopram 20 mg/d for 7 weeks (CN162-007). Inadequate responders were randomized to continue their prospective phase treatment or switch to flexible-dose (0.5-2 mg/d; CN162-006) or fixed-dose (0.25, 0.5, 1, or 2 mg/d; CN162-007) BMS-820836 for 6 weeks. The primary end point in both studies was mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from randomization to study end point. BMS-820836 flexible (0.5-2 mg/d) or fixed dose of 1 mg/d or greater showed efficacy similar to the continuation of antidepressant treatment, with no statistically significant or clinically meaningful differences. In the CN162-006 study, the adjusted mean (SE) change in MADRS total score was -8.7 (0.661) and -8.1 (0.656) for BMS-820836 and duloxetine, respectively (P = 0.526). In the CN162-007 study, the adjusted mean (SE) change in MADRS total score was -7.3 (0.830) and -6.6 (0.842) for BMS-820836 of 1 and 2 mg, respectively, and -6.9 (0.602) for the continuation group (P = 0.910). Thus, BMS-820836 was well tolerated, with no evidence of dose-dependent discontinuations due to adverse events, but it failed to demonstrate superiority to the continuation of an existing antidepressant in patients with treatment-resistant depression.

19 Clinical Trial Olanzapine monotherapy for acute depression in patients with bipolar I or II disorder: results of an 8-week open label trial. 2010

Bobo, William V / Epstein, Richard A / Shelton, Richard C. ·Department of Psychiatry, Vanderbilt University School of Medicine; Nashville, Tennessee 37212, USA. william.v.bobo@vanderbilt.edu ·Hum Psychopharmacol · Pubmed #20029794.

ABSTRACT: We evaluated the efficacy, tolerability, and safety of olanzapine monotherapy in 20 adult patients with bipolar I or II disorder, depressed phase. Patients received open-label olanzapine monotherapy (mean modal dose, 15 mg/day) for 8 weeks. Assessments of psychopathology (Montgomery-Asberg Depression Rating Scale [MADRS], Quick Inventory of Depressive Symptomatology [QIDS-SR-16], Young Mania Rating Scale [YMRS]), clinical global state (Clinical Global Impressions [CGI] scale), and safety/tolerability were performed at baseline, and at 1, 2, 4, 6, and 8 weeks. Seventeen patients (85.0%) completed the study. Improvement in MADRS total scores was observed after the first week of treatment, and at all remaining follow-up time points (p < or = 0.005). Parallel improvement in QIDS-SR-16 (p < 0.001) and CGI-Severity (p < 0.001) was observed between baseline and study endpoint. Nine (45%) subjects achieved positive treatment response, eight of whom (40%) also achieved symptom remission. There were significant increases in weight (+3.2 kg, p = 0.001) and body mass index (+1.1 kg/m(2), p = 0.001), but not fasting glucose or lipids, with the exception of reduced triglyceride levels in the overall sample, and reduced HDL cholesterol in females. Olanzapine may be an effective, well-tolerated option for treating acute non-psychotic depression across a variety of bipolar disorder subtypes.

20 Article Role of Complex Epigenetic Switching in Tumor Necrosis Factor-α Upregulation in the Prefrontal Cortex of Suicide Subjects. 2018

Wang, Qingzhong / Roy, Bhaskar / Turecki, Gustavo / Shelton, Richard C / Dwivedi, Yogesh. ·From the Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham; and the Department of Psychiatry, McGill University, Montreal, Canada. ·Am J Psychiatry · Pubmed #29361849.

ABSTRACT: OBJECTIVE: Proinflammatory cytokines have recently received considerable attention for their role in suicidal behavior; however, how the expression of cytokine genes is regulated is not clearly known. The authors examined underlying mechanisms of critical cytokine gene tumor necrosis factor-alpha (TNF-α) dysregulation in the brains of individuals who died by suicide. METHOD: TNF-α expression was examined in the dorsolateral prefrontal cortex of the postmortem brains of persons with and without major depressive disorder who died by suicide and of persons with major depressive disorder who died of causes other than suicide. The role of putative microRNAs targeting TNF-α and RNA-binding protein Hu antigen R (HuR) was tested with in vitro and in vivo approaches and by examining expression of transactivation response RNA binding protein (TRBP). Genetic influence on TNF-α expression was determined by expression quantitative trait loci analysis and by genotyping three single-nucleotide polymorphisms in the promoter region of the TNF-α gene. Promoter methylation of TNF-α was determined by using methylated DNA immunoprecipitation assay. Expression of miR-19a-3p and TNF-α was also determined in the peripheral blood mononuclear cells of 12 healthy control subjects and 12 currently depressed patients with severe suicidal ideation. RESULTS: TNF-α expression was significantly higher in the dorsolateral prefrontal cortex of individuals who died by suicide, regardless of psychiatric diagnosis. Its expression level was also increased in individuals with major depressive disorder who died by causes other than suicide. On the other hand, expression of miR-19a-3p was upregulated specifically in individuals who died by suicide. In a preliminary observation, similar upregulation of TNF-α and miR-19a-3p was observed in the peripheral blood mononuclear cells of depressed patients with suicidal ideation. Despite its ability to directly target TNF-α in vitro, miR-19a-3p showed no interaction with TNF-α in the dorsolateral prefrontal cortex. HuR potentially stabilized TNF-α transcript, presumably by sequestering its 3' untranslated region from miR-19a-3p-mediated inhibition. Furthermore, decreased TRBP expression supported abnormality in the interaction between miR-19a-3p and TNF-α. Additionally, TNF-α transcriptional upregulation was associated with promoter hypomethylation, whereas no genetic influence on altered TNF-α or miR-19a-3p expression was observed in individuals who died by suicide. CONCLUSIONS: The data in this study provide mechanistic insights into the dysregulation of the TNF-α gene in the brains of individuals who died by suicide, which could potentially be involved in suicidal behavior.

21 Article Double-blind, proof-of-concept (POC) trial of Low-Field Magnetic Stimulation (LFMS) augmentation of antidepressant therapy in treatment-resistant depression (TRD). 2018

Fava, Maurizio / Freeman, Marlene P / Flynn, Martina / Hoeppner, Bettina B / Shelton, Richard / Iosifescu, Dan V / Murrough, James W / Mischoulon, David / Cusin, Cristina / Rapaport, Mark / Dunlop, Boadie W / Trivedi, Madhukar H / Jha, Manish / Sanacora, Gerard / Hermes, Gretchen / Papakostas, George I. ·Massachusetts General Hospital, United States. Electronic address: mfava@mgh.harvard.edu. · Massachusetts General Hospital, United States. · University of Alabama at Birmingham, United States. · Icahn School of Medicine at Mount Sinai, United States. · Emory University, United States. · University of Texas Southwestern, United States. · Yale University, United States. ·Brain Stimul · Pubmed #29030111.

ABSTRACT: BACKGROUND: Low-Field Magnetic Stimulation (LFMS) is a novel, non-invasive, sub-threshold neuromodulation technique, shown in preliminary studies to have immediate mood elevating effects in both unipolar and bipolar depressed patients. OBJECTIVE: We aimed to assess the antidepressant augmentation effects at 48 h of LFMS administered on two consecutive days compared to sham treatment in treatment resistant depression (TRD) subjects, using the Sequential Parallel Comparison Design (SPCD). METHODS: Eighty-four eligible subjects with TRD were randomly assigned to double-blind treatment with LFMS 20 min/day for four days, sham treatment 20 min/day for four days, or sham treatment 20 min/day for 2 days followed by LFMS treatment 20 min/day for two days, using the pre-randomization version of the SPCD (randomization 1:1:1). The SPCD analyses used a repeated measures linear modeling approach with maximum likelihood estimation to use all available data, and using a 60-40 weighting of Stage 1 vs. 2 responses, with the primary outcome being measured after 2 and 4 days. RESULTS: Both primary and secondary outcome measures consistently showed no differences between LFMS-treated patients and those treated with sham, with the exception of a slight, non-significantly greater improvement than sham in the visual analogue scale (VAS) sad mood on LFMS-treated patients. LFMS treatment was relatively well tolerated. CONCLUSIONS: We did not observe a significantly greater, rapid efficacy of LFMS compared to sham therapy. Future studies need to examine the possible therapeutic effects of more intensive forms of LFMS, as other forms of neurostimulation typically require longer duration of exposure.

22 Article Efficacy of Ziprasidone Augmentation of Escitalopram for Cognitive Symptoms of Major Depressive Disorder. 2018

Iovieno, Nadia / Shelton, Richard C / Petrie, Samuel R / Cusin, Cristina / Fava, Maurizio / Papakostas, George I. ·Clinical Trials Network and Institute, Massachusetts General Hospital, One Bowdoin Square, Boston, MA 02114. niovieno@partners.org. · Clinical Trials Network and Institute, Massachusetts General Hospital, Boston, Massachusetts, USA. · University of Alabama-Birmingham Department of Psychiatry and Behavioral Neurobiology, Birmingham, Alabama, USA. · Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. ·J Clin Psychiatry · Pubmed #28749091.

ABSTRACT: OBJECTIVE: To examine the efficacy of adjunctive ziprasidone for cognitive symptoms in adult patients with major depressive disorder (MDD) experiencing persistent symptoms after 8 weeks of open-label escitalopram. METHODS: This post hoc analysis was conducted on a database derived from a previously published study. The parent study was a multicenter, parallel, randomized, double-blind, placebo-controlled trial conducted at 3 academic medical centers in the United States from July 2008 to October 2013. The participant pool consisted of 139 outpatients with persistent symptoms of MDD, according to DSM-IV criteria, following an 8-week open label, flexible-dose trial of escitalopram. Subjects were randomly assigned (1:1, N = 139) to adjunctive fixed-dose ziprasidone (escitalopram + ziprasidone, n = 71) or adjunctive placebo (escitalopram + placebo, n = 68) with 8 weekly follow-up assessments. Primary outcome was clinical response according to the 17-item Hamilton Depression Rating Scale, which was defined as a 50% or greater reduction in scale scores. The Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) was used to measure cognitive and executive dysfunction at each study visit. All statistical testing was conducted at the nominal, 2-sided, 0.05 level of significance. RESULTS: Adjunctive ziprasidone therapy did not result in significantly greater improvement in CPFQ scores compared to adjunctive placebo (P > .05). Residual cognitive symptoms were reported in a substantial number of patients who were considered responders to either adjunctive ziprasidone or placebo. CONCLUSIONS: In the present study, ziprasidone used adjunctively with the selective serotonin reuptake inhibitor escitalopram did not demonstrate a greater efficacy for cognitive symptoms in patients with MDD compared with adjunctive placebo. Future, well-designed studies examining the role of atypical antipsychotics or other augmentation versus switch strategies for cognitive symptoms in MDD are warranted.

23 Article Clinical and Genetic Predictors of Delayed Remission After Multiple Levels of Antidepressant Treatment: Toward Early Identification of Depressed Individuals for Advanced Care Options. 2017

Falola, Michael I / Limdi, Nita / Shelton, Richard C. ·SC 925, 1720 2nd Ave South, Birmingham, AL 35294-0017. mfalola@uabmc.edu. · Department of Psychiatry, The University of Alabama, Birmingham, Alabama, USA. · Department of Neurology, The University of Alabama, Birmingham, Alabama, USA. ·J Clin Psychiatry · Pubmed #29178685.

ABSTRACT: OBJECTIVE: To identify clinical and genetic characteristics that can be used to recognize depressed patients who are likely to respond quickly versus those who will have a more delayed response following multiple treatment trials. METHODS: The data used were obtained from the National Institute of Mental Health-sponsored Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which was conducted between July 2001 and September 2006. Of the 4,041 treatment-naive participants in the original study, 1,953 with DNA samples were included. Major depressive disorder (DSM-IV criteria) was defined as baseline score > 14 on the 17-item Hamilton Depression Rating Scale. Time to remission was defined from the entry point to when a score ≤ 5 on the Quick Inventory of Depressive Symptomatology, Clinician Rating was achieved, irrespective of the type or number of treatments received. A Kaplan-Meier estimator was used for data description, proportional hazard regression for model building, and logistic regression for measures of predictive accuracy. RESULTS: The overall rate of remission across all levels of treatment was 65.6%, and the overall median (interquartile range) of time to remission was 11.4 (6.0-17.9) weeks. The predictors of delayed remission included unemployment (P = .004), severe medical comorbidity (P < .0001), severe baseline depression (P < .0001), more than 4 dysthymic symptoms (P = .005), more than 9 posttraumatic stress symptoms (P = .005), and serotonin receptor 1A (P = .006) and cytochrome P450 2D6 (P = .002 for C/T and P = .0004 for T/T) genetic variants. The final model had good predictive measures of accuracy of area under the curve (70%) and sensitivity (88%). CONCLUSIONS: The results offer clinical tools for clinicians to identify depressed individuals who are likely to have delayed remission with multiple antidepressant treatments and therefore might be candidates for advanced care options.

24 Article Bipolar mixed features - Results from the comparative effectiveness for bipolar disorder (Bipolar CHOICE) study. 2017

Tohen, Mauricio / Gold, Alexandra K / Sylvia, Louisa G / Montana, Rebecca E / McElroy, Susan L / Thase, Michael E / Rabideau, Dustin J / Nierenberg, Andrew A / Reilly-Harrington, Noreen A / Friedman, Edward S / Shelton, Richard C / Bowden, Charles L / Singh, Vivek / Deckersbach, Thilo / Ketter, Terence A / Calabrese, Joseph R / Bobo, William V / McInnis, Melvin G. ·Department of Psychiatry & Behavioral Sciences, University of New Mexico, Health Sciences Center, Albuquerque, NM, USA. Electronic address: mtohen@salud.unm.edu. · Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. · Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. · Lindner Center of HOPE, Mason, OH, USA; Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH, USA. · Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. · Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA. · University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. · Department of Psychiatry, University of Alabama at Birmingham, Birmingham, AL, USA. · Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX, USA. · Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. · Bipolar Disorders Research Center, University Hospital's Case Medical Center, Case Western Reserve University, Cleveland, OH, USA. · Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA. · Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA. ·J Affect Disord · Pubmed #28411507.

ABSTRACT: BACKGROUND: DSM-5 changed the criteria from DSM-IV for mixed features in mood disorder episodes to include non-overlapping symptoms of depression and hypomania/mania. It is unknown if, by changing these criteria, the same group would qualify for mixed features. We assessed how those meeting DSM-5 criteria for mixed features compare to those meeting DSM-IV criteria. METHODS: We analyzed data from 482 adult bipolar patients in Bipolar CHOICE, a randomized comparative effectiveness trial. Bipolar diagnoses were confirmed through the MINI International Neuropsychiatric Interview (MINI). Presence and severity of mood symptoms were collected with the Bipolar Inventory of Symptoms Scale (BISS) and linked to DSM-5 and DSM-IV mixed features criteria. Baseline demographics and clinical variables were compared between mood episode groups using ANOVA for continuous variables and chi-square tests for categorical variables. RESULTS: At baseline, the frequency of DSM-IV mixed episodes diagnoses obtained with the MINI was 17% and with the BISS was 20%. Using DSM-5 criteria, 9% of participants met criteria for hypomania/mania with mixed features and 12% met criteria for a depressive episode with mixed features. Symptom severity was also associated with increased mixed features with a high rate of mixed features in patients with mania/hypomania (63.8%) relative to those with depression (8.0%). LIMITATIONS: Data on mixed features were collected at baseline only and thus do not reflect potential patterns in mixed features within this sample across the study duration. CONCLUSIONS: The DSM-5 narrower, non-overlapping definition of mixed episodes resulted in fewer patients who met mixed criteria compared to DSM-IV.

25 Article DNA methylation and expression of stress related genes in PBMC of MDD patients with and without serious suicidal ideation. 2017

Roy, Bhaskar / Shelton, Richard C / Dwivedi, Yogesh. ·Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. · Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: ydwivedi@uab.edu. ·J Psychiatr Res · Pubmed #28246044.

ABSTRACT: Stress plays an important role in major depressive disorder (MDD) and is one of the state dependent factors in suicidal behavior. A dysfunctional hypothalamic-pituitary-adrenal axis is a common feature in this disorder. The involvement of environmental factors has added additional complexity to understanding depression or suicidal behavior. In this regard, epigenetic regulation has been considered a mechanistic interface between environmental stress stimuli and altered functioning of underlying gene network that may increase susceptibility to depression or suicidal behavior. The present study examined whether epigenetic modifications of stress related genes are associated with MDD and whether there are differences in these epigenetic marks between depressed individuals with and without serious suicidal ideation. Using MeDIP analysis in genomic DNA isolated from peripheral blood mononuclear cells (PBMC) of healthy controls (n = 20), MDD patients with (n = 14) or without serious suicidal ideation (n = 10), we studied methylation of the stress-associated genes, Brain Derived Neurotrophic Factor (BDNF), Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1), FK506 Binding Protein 5 (FKBP5), Corticotropin Releasing Hormone Binding Protein (CRHBP), and Corticotropin Releasing Hormone Receptor 1 (CRHR1). In addition, we determined their transcript levels in RNAs isolated from the same PBMC. We found that BDNF, FKBP5, CRHBP, and NR3C1 gene promoters were significantly hypermethylated in MDD patients with and without suicidal ideation. We also found concomitant reductions in expression of BDNF, FKBP5 transcript variants (1, 2 and 3), and NR3C1 genes in these patients, suggesting that promoter hypermethylation in these genes may functionally be associated with their observed downregulation in MDD patients. In a secondary analysis, methylation of these genes was compared between MDD patients with or without serious suicidal ideation and controls. The MDD with serious suicidal ideation were significantly different from controls while the MDD without were not, although MDD with or without suicidal ideation were not different from each other, likely owning to a relatively small sample size. Thus, our findings underline the importance of epigenetic modifications of stress-associated genes in depression and, possibly, suicidal behavior, which, in future, needs to be confirmed in a larger patient population.